TOWARD A PRACTICAL SYNTHESIS OF MORPHINE - THE FIRST SEVERAL GENERATIONS OF A RADICAL CYCLIZATION APPROACH

A radical cyclization approach to the complete skeleton of morphine wa s investigated in several iterations. The first attempt at a radical c ascade via a Bergman-type intermediate derived from ene-diyne 10 faile d during a model study in which 10-membered silicon-tethered ene-diyne 17 proved inert to Bergman cyclization conditions. A second model stu dy involving ene-diyne 27, functionalized with an allyl group, underwe nt Claisen rearrangement to 32 in preference to a Bergman-type cycliza tion. Several simple model studies were performed with bromophenols ap pended to protected diols 40 and 50, respectively, to determine the fe asibility of C12-C13 bond formation in the former case and the cascade closure C12-C13/C14-C9 in the latter via radical species generated fr om the aryl halides. The second-generation approach employed the diene diol 7a derived biocatalytically from beta-bromoethylbenzene via oxid ation with E. coli JM109(pDTG601), its conversion to cyclization precu rsor 55, and the radical cyclization to 56a,b. The conditions and the outcome of this process are discussed in detail along with the rationa lization of stereochemistry of the cyclization, which furnished C14-ep i configuration in 56a in low yield. The third-generation synthesis re lied on stepwise radical cyclization of vinyl bromide 67 derived from o-bromo-beta-ethylbenzene (also by biocatalytic means) and equipped wi th an oxazolidone as the radical acceptor group. Isoquinoline derivati ves 68a and 68b were obtained as a mixture of isomers, the major of wh ich, 68a, was converted via a second tin-mediated cyclization to the p entacyclic compound 78, also possessing C14-epi configuration. The ste pwise radical cyclization proceeded in higher yields, produced cleaner reaction mixtures, and was also performed with the more flexible alco hol 87, whose tin-mediated closure produced a 1:1 mixture of C14 epime rs, tetracyclic compounds 81 and 89. Finally, tetracycle 80 or pentacy cle 79 was converted to oxo aldehyde 83 and cyclized to the complete m orphinan skeleton, 84, in the ent-C14-epi series. Additionally, prelim inary studies were performed on direct closures of chloride 82 to 85, via a C10/C11 alkylation of a sp(3)-hybridized center. The three gener ations of synthetic effort are discussed in detail and physical and sp ectral data are provided for all new compounds. The relative merits of tandem vs. stepwise radical cyclization are evaluated and projections for future work are indicated.